Alzheimer's disease (AD) is a progressive, chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. Alzheimer's disease is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person's daily life and activities. In its early stages, memory loss is mild, but with late-stage AD, individuals lose the ability to carry on a conversation and respond to their environment. If untreated, AD ultimately leads to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.
AD is a polygenic/multifactorial complex disorder characterized by the premature death of neurons. Although the amyloid hypothesis is recognized as the Primum Movens of AD pathogenesis, mutational genetics associated with amyloid precursor protein (APP) and presenilin (PS) genes lone does not explain in full the neuropathologic findings present in AD, represented by amyloid deposition in senile plaques and vessels (amyloid angiopathy), neurofibrillary tangle (NFT) formation due to hyperphosphorylation of tau protein, synaptic and dendritic desarborization and neuronal loss. These findings are companied by neuroinflammatory reactions, oxidative stress, and free radical formation probably associated with mitochondrial dysfunction, excitotoxic reactions, alterations in cholesterol metabolism and lipid rafts, deficiencies in neurotransmitters (especially acetylcholine) and neurotrophic factor function, defective activity of the ubiquitin-proteasome, and chaperone systems and cerebrovascular dysregulation. All these neurochemical events are potential targets for treatment; however, it is very unlikely that a single drug be able alone to neutralize the complex mechanisms involved in neurodegeneration.
In the early 1980s it was believed that AD-related memory dysfunction was in part due to a cholinergic deficit in the brain of affected people due to a loss of neurons in the basal forebrain, this giving rise to the cholinergic hypothesis of AD. Since choline donors (precursors) and acetylcholine itself were substances of difficult pharmacological management (or useless to increase brain cholinergic neurotransmission), and, paradoxically, considering that acetylcholinesterase activity progressively decreased in AD brains in parallel with cognitive deterioration, AChEIs were proposed as an option to inhibit acetylcholine degradation in the synaptic cleft and to increase choline reuptake at the presynaptic level with the aim of enhancing acetylcholine synthesis in presynaptic terminals, this facilitating cholinergic neurotransmission. The first candidate to fulfil this criteria was tacrine (tetrahydroaminoacridine) which after its introduction in the market in 1993 soon fell out of favor due to its hepatotoxicity and poor tolerability; 3 years later, in 1996, donepezil was approved by the FDA for the treatment of mild-to-moderate cases of AD. The other AChEIs, rivastigmine and galantamine, were introduced several years later.
However, acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine will not cure AD or prevent the loss of these abilities at some time in the future. So AD has no current cure, and our effort is to find better ways to reverse the disease, delay and prevent it from developing.
On the other hand, the genetic, cellular, and molecular changes associated with AD support the evidence that activated immune and inflammatory processes is a part of the disease. Also a strong benefit of long-term use of NSAIDs was shown in epidemiological studies. So it is generally accepted that AD is partially an inflammatory disease and that inhibiting inflammation is an option of treating AD.
Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, micro-localized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, micro-localized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies so far strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immune-regulatory processes, it should be possible to develop anti-inflammatory approaches that may reverse or delay or prevent developing of this devastating disorder.
Azelastine is classified pharmacologically as a second generation antihistamine and is a relatively selective, nonsedating, competitive antagonist at H1 receptors. More uniquely, its inhibition of inflammatory mediators, in addition to antihistaminic and mast cell stabilizing effects, places it among the new generation of dual-acting anti-inflammatory drugs. Its ability to modify several other mediators of inflammation and allergy contributes to its mechanism of action. In vitro and in vivo studies, as well as clinical trials support the dual effects of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that azelastine's affinity for inhibition of mast cell degranulation may also decrease the release of other inflammatory mediators, including leukotrienes and interleukin-1β, among others. Azelastine also directly antagonizes other mediators of inflammation, such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet-activating factor. Therefore, a unique combination of azelastine and donepezil and/or rivastigmine and/or galantamine is expected to be, in terms of creating synergistic effects, innovative potential treatments for AD.